CN1254496C - Method of preparing branched polyethylene glycol - Google Patents
Method of preparing branched polyethylene glycol Download PDFInfo
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- CN1254496C CN1254496C CN 02120740 CN02120740A CN1254496C CN 1254496 C CN1254496 C CN 1254496C CN 02120740 CN02120740 CN 02120740 CN 02120740 A CN02120740 A CN 02120740A CN 1254496 C CN1254496 C CN 1254496C
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Abstract
The present invention provides a method for preparing branched polyethylene glycol. The present invention has the steps that first, amino acid benzoic acid and carboxy methylation single methoxypolyethylene glycol are respectively prepared; then, after the amino acid benzoic acid and the carboxy methylation single methoxypolyethylene glycol are uniformly mixed, TEA, DCC and NHS are orderly added in the mixture; after products obtained after reaction carry out gel filtration separation, the branched polyethylene glycol can be obtained. The branched polyethylene glycol has the advantage of wide application, can be used for modifying isocytosis protein molecules, and can be used for modifying small molecule medicine and surfaces. The method of the present invention has the advantages of simplicity and easy operation, only lysine carboxyl needs to be protected, activated amino and carboxyl are not needed, the reaction is carried out under room temperature, the pH value does not need to be controlled, used raw materials and chemical agents have low price, and the yield is as high as about 65%.
Description
Technical field
The invention belongs to biomedical and protein chemistry field, particularly a kind of method for preparing branched polyethylene glycol.
Background technology
Along with the fast development of biotechnology, the polypeptide of more and more biologically actives, protein, enzyme is used for clinical treatment by people.Yet these biomacromolecules exist some defectives when directly applying to human body.These defectives comprise: 1. get rid of fast, 2. biological degradation 3. causes immune response or the like.Therefore, protein particularly the chemically modified of medical protein remain the research field of a hot topic so far.Many natural and synthetic molecules are used as chemically modified.This synthetic molecule of polyoxyethylene glycol has the advantages such as antigenicity that can reduce by modifier and is widely used in protein, polypeptide, the modification of enzyme even some small-molecule drugs because its biocompatibility is nontoxic to human body.
Polyoxyethylene glycol (PEG) is a kind of water miscible polymkeric substance.When with protein (also having polypeptide, enzyme and other biological bioactive molecule) covalent attachment, polyoxyethylene glycol can remedy the deficiency of these protein molecules itself, enlarges its potential and uses.Compare with the protein contrast of unmodified, the pharmacological property that PEG-protein conjugate this improved has excited people to develop the enthusiasm of this binding substances as preparation.For example, the PEG-adenosine deaminase has obtained the approval of FDA; The cytokine that PEG modifies is made into, and the GM-CSF (macrophage colony stimulating factor) that PEG modifies has shown two kinds of unconnected biological properties.It is found that under study for action PEG is relevant to the molecular weight of the modification effect of biologically active substance and employed PEG molecule and specific modification degree.In general, the molecular weight of used PEG is big more, and modification degree is high more, and the antigenicity of PEG-protein conjugate is more little, and the eliminating time is long more, but the biological activity of binding substances can reduce simultaneously.This bioactive reduction mainly causes owing to excessive grooming.In order to address this problem, people have synthesized ramiform PEG molecule.With ramiform PEG modifying protein, compare with straight chain PEG molecule, under the identical situation of modification degree, the PEG molecular weight of connection then can be multiplied.This increase is with respect to straight chain PEG, have two advantages: 1. enlarge the binding substances molecular size, the eliminating time in the extension body, 2. ramiform PEG can more effectively check contacting of hydrolase and antibody and protein-PEG binding substances, avoids being hydrolyzed and causing immune response.Therefore, under the situation that has identical modification degree, the modification effect of ramiform PEG is more much better than straight chain PEG.
Ramiform PEG's is synthetic because the difference of initiator has several different route of synthesis:
1. initiator is mPEG-OH, and its synthetic route is:
Defective is the agents useful for same costliness, and synthesis step is many;
2. initiator is mPEG-CHO, and its synthetic route is:
Defective is that productive rate is very low, and product is difficult to be separated:
3. initiator is mPEG-COOH, and its synthetic route is
Though it is higher that defective is productive rate, the difficult control of reaction conditions;
The above-mentioned defective of above-mentioned synthetic method causes the valuable product of branched polyethylene glycol, has limited the application of branched polyethylene glycol in research and practice to a great extent.
Summary of the invention
The objective of the invention is in order to overcome many defectives that the above-mentioned method for preparing branched polyethylene glycol exists, and a kind of new method for preparing branched polyethylene glycol is provided.
Branched polyethylene glycol has the single functional group that activates, and structurally is two substitution products of two PEG-COOH molecules for the Methionin molecule, and its molecule is:
Technical scheme of the present invention is as follows:
The method for preparing branched polyethylene glycol provided by the invention, its processing step is as follows:
1, preparation ethyl ester of lysine hydrochloride
Methionin is dissolved in dehydrated alcohol, feeds the exsiccant hydrogen chloride gas to saturated under agitation condition, reflux makes the Methionin dissolving, this solution is placed spent the night; Excess ethanol and hydrogenchloride are removed in underpressure distillation then; Use anhydrous diethyl ether at last, carry out the crystallization of ethyl ester of lysine hydrochloride; Again after filtration, washing, drying obtains ethyl ester of lysine hydrochloride light yellow crystal;
2, prepare carboxymethylated mono methoxy polyethylene glycol
MPEG is dissolved in the exsiccant methylene dichloride, adds activatory Manganse Dioxide, behind the uniform mixing, stir under the room temperature and spend the night; Remove by filter catalyzer, obtain intermediate oxidation product by the pressure reducing and steaming solvent;
It is 3% aqueous hydrogen peroxide solution that the intermediate oxidation product that obtains is dissolved in volume ratio, reacts after 24 hours, by Bio-Rad AG1*2 resin column, removes neutral substance, uses 0.02M HCl wash-out again, obtains carboxymethylated mono methoxy polyethylene glycol;
3, preparation branched polyethylene glycol
1) with the carboxymethylated mono methoxy polyethylene glycol of the ethyl ester of lysine hydrochloride of step 1 gained and step 2 gained with 1: the mol ratio of 2-4 is dissolved in the dry methylene chloride, add excessive triethylamine then, dicyclohexylcarbodiimide, nitrogen-N-Hydroxysuccinimide, reaction removed by filter the dicyclohexylurea (DCU) that is generated after 24 hours under the room temperature; Add the cold diethyl ether precipitation then, obtain the white powder product; The white powder product that obtains is dissolved in 1N NaOH, adds sodium-chlor, react after 1-2 hour, solution is transferred to pH=3 with hydrochloric acid; Then with dichloromethane extraction at least 3 times, organic phase that will the extraction gained merges, and use anhydrous magnesium sulfate drying, and underpressure distillation concentrates, and adds cold diethyl ether and precipitates, and obtains the material of white powder.
2) with above-mentioned products therefrom, per 0.2 gram is dissolved in 1 ml water, and use BiogelP100 (100-200mesh) 5*50 chromatography column to carry out with water is the wash-out separation of elutriant in batches, and every pipe is collected component for 10 milliliters; To merge with respect to the component of branched polyethylene glycol, concentrate, use the methylene dichloride extracting then, ether sedimentation is used alcohol crystal at last, obtains the branched polyethylene glycol of purifying;
Described Methionin is L-Methionin; Described mPEG is that relative molecular mass is the mono methoxy polyethylene glycol between the 750-10000.
The branched polyethylene glycol of method preparation of the present invention can be used for biomacromolecules such as modifying protein, also can modify small-molecule drug and other surfaces.
The present invention has following characteristics:
1, invention connects the peptide principle in synthesizing based on polypeptide, only needs the carboxyl of protection Methionin, does not need activatory amino and carboxyl;
2, be reflected at room temperature and carry out, need not control the pH value;
3, raw materials used and reagent low price;
4, be reflected in the organic phase and carry out;
5, productive rate height can reach 65%.
Description of drawings
Accompanying drawing 3 is the infrared spectrum of preparation method's of the present invention step 2 products therefrom; Its characteristic absorbance is 1745.50cm
-1(absorption of sour carbonyl);
Accompanying drawing 4 is the MALDI-TOF spectrogram of preparation method's of the present invention step 3 products therefrom;
Accompanying drawing 5 is the GPC spectrogram of preparation method's of the present invention step 3 products therefrom;
Accompanying drawing 6 is for preparation method's of the present invention purpose product
1H NMR spectrogram;
Embodiment
1, preparation ethyl ester of lysine hydrochloride
L Methionin is dissolved in dehydrated alcohol, feeds the exsiccant hydrogen chloride gas to saturated under agitation condition, reflux makes the dissolving of L-Methionin, this solution is placed spent the night; Excess ethanol and hydrogenchloride are removed in underpressure distillation then; Use anhydrous diethyl ether at last, carry out the crystallization of ethyl ester of lysine hydrochloride; Again after filtration, washing, drying obtains ethyl ester of lysine hydrochloride light yellow crystal;
2, the preparation molecular weight is 5000 carboxymethylated mono methoxy polyethylene glycol
MPEG5000 is dissolved in the exsiccant methylene dichloride, adds activatory Manganse Dioxide, behind the uniform mixing, stir under the room temperature and spend the night; Remove by filter catalyzer, obtain intermediate oxidation product by the pressure reducing and steaming solvent;
It is 3% aqueous hydrogen peroxide solution that the intermediate oxidation product that obtains is dissolved in volume ratio, react after 24 hours,, remove neutral substance by Bio-Rad AG1*2 resin column, use 0.02M HCl wash-out again, obtain molecular weight and be 5000 carboxymethylated mono methoxy polyethylene glycol;
3, the branched polyethylene glycol of preparation purifying
1) being 5000 carboxymethylated mono methoxy polyethylene glycol with the molecular weight of the ethyl ester of lysine hydrochloride of step 1 gained and step 2 gained is dissolved in the dry methylene chloride with 1: 2 mol ratio, add excessive triethylamine then, dicyclohexylcarbodiimide, nitrogen-N-Hydroxysuccinimide, reaction removed by filter the dicyclohexylurea (DCU) that is generated after 24 hours under the room temperature; Add the cold diethyl ether precipitation then, obtain the white powder product; The white powder product that obtains is dissolved in 1N NaOH, adds sodium-chlor, react after 1-2 hour, solution is transferred to pH=3 with hydrochloric acid; Use dichloromethane extraction then 3 times, with the organic phase merging of extraction gained, and use anhydrous magnesium sulfate drying, underpressure distillation concentrates, and adds the cold diethyl ether precipitation, obtains the material of white powder;
MALDI-TOF (Fig. 3) spectrogram shows: this product is that molecular weight is that 5000 carboxymethylated single first chlorine polyoxyethylene glycol and molecular weight are the mixture of carboxymethylated single first chlorine polyoxyethylene glycol of 10000; The GPC spectrogram shows: the productive rate of ramiform PEG is 61%;
2) with above-mentioned products therefrom, per 0.2 gram is dissolved in 1 ml water, and use BiogelP100 (100-200mesh) 5*50 chromatography column to carry out with water is the wash-out separation of elutriant in batches, and every pipe is collected component for 10 milliliters; To merge with respect to the component of branched polyethylene glycol, concentrate, use the methylene dichloride extracting then, ether sedimentation is used alcohol crystal at last, obtains the purpose product branched polyethylene glycol of purifying.
The structure of purpose product can pass through MALDI-TOF (Fig. 3) spectrogram and
1H NMR (Fig. 6) confirms.
1, preparation ethyl ester of lysine hydrochloride
L Methionin is dissolved in dehydrated alcohol (1: 8 mol ratio), feeds the exsiccant hydrogen chloride gas to saturated under agitation condition, reflux makes the dissolving of L-Methionin, this solution is placed spent the night; Excess ethanol and hydrogenchloride are removed in underpressure distillation then; Use anhydrous diethyl ether at last, carry out the crystallization of ethyl ester of lysine hydrochloride; Again after filtration, washing, drying obtains ethyl ester of lysine hydrochloride light yellow crystal;
2, the preparation molecular weight is 2000 carboxymethylated mono methoxy polyethylene glycol
The mPEG2000 of 25 grams is dissolved in the exsiccant methylene dichloride, adds 20 gram activatory Manganse Dioxide, behind the uniform mixing, stir under the room temperature and spend the night; Remove by filter catalyzer, obtain intermediate oxidation product by the pressure reducing and steaming solvent;
It is 3% aqueous hydrogen peroxide solution that the intermediate oxidation product that obtains is dissolved in volume ratio, react after 24 hours,, remove neutral substance by Bio-Rad AG1*2 resin column, use 0.02M HCl wash-out again, obtain molecular weight and be carboxymethylated single first chlorine polyoxyethylene glycol of 2000;
3, the branched polyethylene glycol of preparation purifying
1) being 2000 carboxymethylated mono methoxy polyethylene glycol with the molecular weight of the ethyl ester of lysine hydrochloride of step 1 gained and step 2 gained is dissolved in the dry methylene chloride with 1: 4 mol ratio, add excessive triethylamine then, dicyclohexylcarbodiimide, nitrogen-N-Hydroxysuccinimide, reaction removed by filter the dicyclohexylurea (DCU) that is generated after 24 hours under the room temperature; Add the cold diethyl ether precipitation then, obtain white powder product 9.5 grams; The white powder product that obtains is dissolved in 1N NaOH, adds sodium-chlor, react after 1-2 hour, solution is transferred to pH=3 with hydrochloric acid; Use dichloromethane extraction then 5 times,, and after using anhydrous magnesium sulfate drying, underpressure distillation to be concentrated into 50 milliliters, add the cold diethyl ether precipitation, obtain material 9.0 grams of white powder the organic phase merging of extraction gained;
MALDI-TOF (Fig. 3) spectrogram shows: this product is that molecular weight is that 2000 carboxymethylated mono methoxy polyethylene glycol and molecular weight are the mixture of carboxymethylated single first chlorine polyoxyethylene glycol of 4000; The GPC spectrogram shows: the productive rate of ramiform PEG is 61%;
2) with above-mentioned products therefrom, per 0.2 gram is dissolved in 1 ml water, and use BiogelP100 (100-200mesh) 5*50 chromatography column to carry out with water is the wash-out separation of elutriant in batches, and every pipe is collected component for 10 milliliters; To merge with respect to the component of branched polyethylene glycol, concentrate, use the methylene dichloride extracting then, ether sedimentation is used alcohol crystal at last, obtains the purpose product branched polyethylene glycol of purifying.
The structure of purpose product can pass through MALDI-TOF (Fig. 3) spectrogram and
1H NMR (Fig. 6) confirms.
1, preparation ethyl ester of lysine hydrochloride
L Methionin is dissolved in dehydrated alcohol, feeds the exsiccant hydrogen chloride gas to saturated under agitation condition, reflux makes the dissolving of L-Methionin, this solution is placed spent the night; Excess ethanol and hydrogenchloride are removed in underpressure distillation then; Use anhydrous diethyl ether at last, carry out the crystallization of ethyl ester of lysine hydrochloride; Again after filtration, washing, drying obtains ethyl ester of lysine hydrochloride light yellow crystal;
2, the preparation molecular weight is 750 carboxymethylated mono methoxy polyethylene glycol
MPEG750 is dissolved in the exsiccant methylene dichloride, adds activatory Manganse Dioxide, behind the uniform mixing, stir under the room temperature and spend the night; Remove by filter catalyzer, obtain intermediate oxidation product by the pressure reducing and steaming solvent;
It is 3% aqueous hydrogen peroxide solution that the intermediate oxidation product that obtains is dissolved in volume ratio, react after 24 hours,, remove neutral substance by Bio-Rad AG1*2 resin column, use 0.02M HCl wash-out again, obtain molecular weight and be carboxymethylated single first chlorine polyoxyethylene glycol of 750;
3, the branched polyethylene glycol of preparation purifying
1) being 5000 carboxymethylated mono methoxy polyethylene glycol with the molecular weight of the ethyl ester of lysine hydrochloride of step 1 gained and step 2 gained is dissolved in the dry methylene chloride with 1: 2 mol ratio, add excessive triethylamine then, dicyclohexylcarbodiimide, nitrogen-N-Hydroxysuccinimide, reaction removed by filter the dicyclohexylurea (DCU) that is generated after 24 hours under the room temperature; Add the cold diethyl ether precipitation then, obtain the white powder product; The white powdery product that obtains is dissolved in 1N NaOH, adds sodium-chlor, react after 1-2 hour, solution is transferred to pH=3 with hydrochloric acid; Use dichloromethane extraction then 3 times, with the organic phase merging of extraction gained, and use anhydrous magnesium sulfate drying, underpressure distillation concentrates, and adds the cold diethyl ether precipitation, obtains the material of white powder;
MALDI-TOF (Fig. 3) spectrogram shows: this product is that molecular weight is that 750 carboxymethylated mono methoxy polyethylene glycol and molecular weight are the mixture of 15000 carboxymethylated mono methoxy polyethylene glycol; The GPC spectrogram shows: the productive rate of ramiform PEG is 61%;
2) with above-mentioned products therefrom, per 0.2 gram is dissolved in 1 ml water, and use BiogelP100 (100-200mesh) 5*50 chromatography column to carry out with water is the wash-out separation of elutriant in batches, and every pipe is collected component for 10 milliliters; To merge with respect to the component of branched polyethylene glycol, concentrate, use the methylene dichloride extracting then, ether sedimentation is used alcohol crystal at last, obtains the purpose product branched polyethylene glycol of purifying.
The structure of purpose product can pass through MALDI-TOF (Fig. 3) spectrogram and
1H NMR (Fig. 6) confirms.
1, preparation ethyl ester of lysine hydrochloride
L Methionin is dissolved in dehydrated alcohol, feeds the exsiccant hydrogen chloride gas to saturated under agitation condition, reflux makes the dissolving of L-Methionin, this solution is placed spent the night; Excess ethanol and hydrogenchloride are removed in underpressure distillation then; Use anhydrous diethyl ether at last, carry out the crystallization of ethyl ester of lysine hydrochloride; Again after filtration, washing, drying obtains ethyl ester of lysine hydrochloride light yellow crystal;
2, the preparation molecular weight is 10000 carboxymethylated mono methoxy polyethylene glycol
MPEG10000 is dissolved in the exsiccant methylene dichloride, adds activatory Manganse Dioxide, behind the uniform mixing, stir under the room temperature and spend the night; Remove by filter catalyzer, obtain intermediate oxidation product by the pressure reducing and steaming solvent;
It is 3% aqueous hydrogen peroxide solution that the intermediate oxidation product that obtains is dissolved in volume ratio, react after 24 hours,, remove neutral substance by Bio-Rad AG1*2 resin column, use 0.02M HCl wash-out again, obtain molecular weight and be 10000 carboxymethylated mono methoxy polyethylene glycol;
3, the branched polyethylene glycol of preparation purifying
1) being 10000 carboxymethylated mono methoxy polyethylene glycol with the molecular weight of the ethyl ester of lysine hydrochloride of step 1 gained and step 2 gained is dissolved in the dry methylene chloride with 1: 2 mol ratio, add excessive triethylamine then, dicyclohexylcarbodiimide, nitrogen-N-Hydroxysuccinimide, reaction removed by filter the dicyclohexylurea (DCU) that is generated after 24 hours under the room temperature; Add the cold diethyl ether precipitation then, obtain the white powder product; The white powder product that obtains is dissolved in 1N NaOH, adds sodium-chlor, react after 1-2 hour, solution is transferred to pH=3 with hydrochloric acid; Use dichloromethane extraction then 4 times, with the organic phase merging of extraction gained, and use anhydrous magnesium sulfate drying, underpressure distillation concentrates, and adds the cold diethyl ether precipitation, obtains the material of white powder;
MALDI-TOF (Fig. 3) spectrogram shows: this product is that molecular weight is that 10000 carboxymethylated mono methoxy polyethylene glycol and molecular weight are the mixture of 20000 branching type polyoxyethylene glycol; The GPC spectrogram shows: the productive rate of ramiform PEG is 61%;
2) with above-mentioned products therefrom, per 0.2 gram is dissolved in 1 ml water, and use BiogelP100 (100-200mesh) 5*50 chromatography column to carry out with water is the wash-out separation of elutriant in batches, and every pipe is collected component for 10 milliliters; To merge with respect to the component of branched polyethylene glycol, concentrate, use the methylene dichloride extracting then, ether sedimentation is used alcohol crystal at last, obtains the purpose product branched polyethylene glycol of purifying.
The structure of purpose product can pass through MALDI-TOF (Fig. 3) spectrogram and
1H NMR (Fig. 6) confirms.
Claims (3)
1, a kind of method for preparing branched polyethylene glycol, its processing step is as follows:
1) preparation ethyl ester of lysine hydrochloride
Methionin is dissolved in dehydrated alcohol, feeds the exsiccant hydrogen chloride gas to saturated under agitation condition, reflux makes the Methionin dissolving, this solution is placed spent the night; Excess ethanol and hydrogenchloride are removed in underpressure distillation then; Use anhydrous diethyl ether at last, carry out the crystallization of ethyl ester of lysine hydrochloride; Again after filtration, washing, drying obtains ethyl ester of lysine hydrochloride light yellow crystal;
2) prepare carboxymethylated mono methoxy polyethylene glycol
MPEG is dissolved in the exsiccant methylene dichloride, adds activatory Manganse Dioxide, behind the uniform mixing, stir under the room temperature and spend the night; Remove by filter catalyzer, obtain intermediate oxidation product by the pressure reducing and steaming solvent;
It is 3% aqueous hydrogen peroxide solution that the intermediate oxidation product that obtains is dissolved in volume ratio, reacts after 24 hours, by Bio-Rad AG1*2 resin column, removes neutral substance, uses 0.02M HCl wash-out again, obtains carboxymethylated mono methoxy polyethylene glycol;
3) branched polyethylene glycol of preparation purifying
(1) with the carboxymethylated mono methoxy polyethylene glycol of the ethyl ester of lysine hydrochloride of step 1) gained and step 2 gained with 1: the mol ratio of 2-4 is dissolved in the dry methylene chloride, add excessive triethylamine then, dicyclohexylcarbodiimide, nitrogen-N-Hydroxysuccinimide, reaction removed by filter the dicyclohexylurea (DCU) that is generated after 24 hours under the room temperature; Add the cold diethyl ether precipitation then, obtain the white powder product; The white powder product that obtains is dissolved in 1N NaOH, adds sodium-chlor, react after 1-2 hour, solution is transferred to pH=3 with hydrochloric acid; Then with dichloromethane extraction at least 3 times, organic phase that will the extraction gained merges, and use anhydrous magnesium sulfate drying, and underpressure distillation concentrates, and adds cold diethyl ether and precipitates, and obtains the material of white powder;
(2) with above-mentioned products therefrom, per 0.2 gram is dissolved in 1 ml water, and use BiogelP100 (100-200mesh) 5*50 chromatography column to carry out with water is the wash-out separation of elutriant in batches, and every pipe is collected component for 10 milliliters; To merge with respect to the component of branched polyethylene glycol, concentrate, use the methylene dichloride extracting then, ether sedimentation is used alcohol crystal at last, obtains the branched polyethylene glycol of purifying.
2, by the described method for preparing branched polyethylene glycol of claim 1, it is characterized in that described amino acid is L-Methionin.
3, by the described method for preparing branched polyethylene glycol of claim 1, it is characterized in that described mPEG is that relative molecular mass is the polymkeric substance between the 750-10000.
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| CN 02120740 CN1254496C (en) | 2002-05-30 | 2002-05-30 | Method of preparing branched polyethylene glycol |
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| CN 02120740 CN1254496C (en) | 2002-05-30 | 2002-05-30 | Method of preparing branched polyethylene glycol |
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Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN100475837C (en) * | 2004-06-11 | 2009-04-08 | 北京键凯科技有限公司 | Branched polyglycol-amino acid oligopeptide and active derivative and medicinal composition thereof |
| CN101002943B (en) * | 2006-01-17 | 2012-02-01 | 中国科学院过程工程研究所 | Conjugate of branched chain PEG-GCSF and PEG-GMCSF, and its preparing method |
| CN100543063C (en) * | 2006-04-03 | 2009-09-23 | 中国科学院过程工程研究所 | Polyethyleneglycol of end group of amino acid and preparation method thereof |
| CN101168594B (en) * | 2006-10-24 | 2011-07-27 | 北京键凯科技有限公司 | Polyglycol active derivative with oligopeptide as framework, preparation method thereof and conjugate of with pharmaceutical molecule |
| CN101176791B (en) * | 2006-11-07 | 2013-01-09 | 中国药科大学 | Amino acid communicating with polyglycol as well as manufacturing method and usage thereof |
| CN102731632B (en) * | 2012-07-16 | 2014-03-12 | 张喜田 | Recombinant ganoderma immunomodulatory protein monomethoxypolyglycol succinimidyl propionate modifier, preparation method and use thereof |
| CN104892927A (en) * | 2015-05-18 | 2015-09-09 | 湖南华腾制药有限公司 | A preparing method of branch type mPEG |
| CN105288649A (en) * | 2015-10-14 | 2016-02-03 | 湖南华腾制药有限公司 | Paclitaxel modified by branched polyethylene glycol and preparation method of paclitaxel |
| CN107459640A (en) * | 2017-08-14 | 2017-12-12 | 湖南华腾制药有限公司 | A kind of isolation and purification method of Amino End Group polyethylene glycol hydroxyl |
| CN114085233A (en) * | 2021-10-08 | 2022-02-25 | 苏州凯润纳米材料有限公司 | Polyethylene glycol linking agent for protein modification and synthesis method thereof |
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